DESCRIPTION: (Applicant's Abstract) Activity-dependent processes that modify the strength of synaptic transmission are thought to play a crucial role in the formation of new memories during learning and in the refinement of synaptic connections that occurs during development. In the hippocampus, a region of the brain known to have a crucial role in memory formation, excitatory synapses express a number of different forms of synaptic plasticity. For instance, some patterns of synaptic activity induce a long-lasting enhancement of synaptic transmission known as long-term potentiation (LTP) while different patterns of activity can induce a long-lasting decrease in transmission known as long-term depression (LTD). The synaptic events leading to LTP and LTD induction are well characterized and key components of the signaling pathways responsible for these forms of plasticity have been identified. Little is known, however, about how the signaling pathways responsible for LTP and LTD interact to generate the "rules" that determine how synaptic strength is modified by different patterns of synaptic activity. In this project we will use synaptic stimulation protocols that mimic endogenous patterns of neural activity in the hippocampus to investigate the cellular and molecular mechanisms that regulate LTP induction at excitatory synapses onto hippocampal pyramidal cells. In particular, we will investigate the role of activity-dependent changes in NMDA-type glutamate receptor function, nitric oxide production, and cAMP signaling in the ability of certain patterns of synaptic stimulation to disrupt the induction of LTP. In addition, we will investigate synaptic transmission and plasticity in transgenic mice with a mutation in the postsynaptic density protein PSD-95, a protein thought to be an important organizer of NMDA receptor-dependent signaling pathways involved in synaptic plasticity. These experiments will provide insights into the cellular and molecular mechanisms controlling forms of synaptic plasticity thought to be involved in learning and memory and may provide insights into how changes in these processes might contribute to the impairment of memory formation that occurs in Alzheimer's disease and during normal aging.